A T-cell antigen atlas for meningioma: novel options for immunotherapy.

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma.

Anatomical phenotyping and staging of brain tumours.

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.

Trends in Literature on Cerebral Bypass Surgery: A Systematic Review.

INTRODUCTION: Ever since the beginning of cerebral bypass surgery, the role of the bypass has been debated and indications have changed over the last 5 decades. This systematic literature research analysed all clinical studies on cerebral bypass that have been published from January 1959 to January 2020 for their year of publication, country of origin, citation index, role of and indication for bypass, bypass technique, revascularized territory, flow capacity, and title (for word cloud analysis per decade). METHODS: A systematic literature research was conducted using PubMed, Web of Science, EMBASE, and SCOPUS databases. All studies that have been published until January 1, 2020, were included. RESULTS: Of 6,013 identified studies, 2,585 were included in the analysis. Of these, n = 1,734 (67%) studies addressed flow-augmentation bypass and n = 701 (27%) addressed flow-preservation bypass. The most common indication reported for flow augmentation is moyamoya (n = 877, 51%), followed by atherosclerotic steno-occlusive disease (n = 753, 43%). For flow preservation, the most common indication is studies reporting on cerebral aneurysm surgery (n = 659, 94%). The increasing popularity of reporting on these bypass operations almost came to an end with the FDA approval of flow diverters for aneurysm treatment in 2011. Japan is the country with the most bypass studies (cumulatively published 933 articles), followed by the USA (630 articles) and China (232 articles). DISCUSSION/CONCLUSION: Clinical studies on cerebral bypass surgery have become increasingly popular in the past decades. Since the introduction of moyamoya as a distinct pathologic entity, Asian countries in particular have a very active community regarding this disease, with an increasing number of articles published every year. Studies on bypass for chronic steno-occlusive disease peaked in the 1980s but have remained the main focus of bypass research, particularly in many European departments. The number of reports published on these bypass operations significantly decreased after the FDA approval of flow diverters for aneurysm treatment in 2011.

Preoperative risk factors associated with new focal neurological deficit and other major adverse events in first-time intracranial meningioma neurosurgery.

BACKGROUND: Neurosurgical resection is the mainstay of meningioma treatment. Adverse event (AE) rates of meningioma resections are significant, but preoperative risk factors for major AEs in patients undergoing first-time meningioma surgery are largely unknown. The aim of this study was to explore major AEs and identify preoperative risk factors in patients undergoing first-time meningioma surgery. METHODS: Data on all meningioma resections performed at the University Hospital Zurich from 1 January 2013 to 31 December 2018 were collected in a prospective registry. All AEs that occurred within 3 months of surgery were documented in detail and classified as "minor" or "major." Statistical analysis included initial individual bivariate analyses of all preoperative factors and the occurrence of major AEs. Statistically significant variables were then included in a logistic regression model to identify predictors. RESULTS: Three hundred forty-five patients were included in the study. Mean age was 58.1 years, and 77.1% of patients were female. The overall major AE rate was 20.6%; the most common of which was a new focal neurological deficit (12.8% of patients). Six preoperative factors showed a significant association with the occurrence of major AEs in bivariate analysis. All variables included in the logistic regression model showed increased odds of occurrence of major AE, but only tumor complexity as measured by the Milan Complexity Scale was a statistically significant predictor, with a score of 4 or more having twice the odds of major AEs (OR: 2.00, 95% CI: 1.15-3.48). CONCLUSION: High tumor complexity is an independent predictor of the occurrence of major AEs following meningioma resection. Preoperative assessment of tumor complexity using the Milan Complexity Scale is warranted and can aid communication with patients about AE rates and surgical decision-making.

Distinct topographic-anatomical patterns in primary and secondary brain tumors and their therapeutic potential.

PURPOSE: Understanding the topographic-anatomical patterns of brain tumors has the potential to improve our pathophysiological understanding and may allow for anatomical tailoring of surgery and radiotherapy. This study analyzed topographic-anatomical patterns underlying neuroepithelial tumors, primary CNS lymphoma and metastases. METHODS: Any histologically confirmed supra- or infratentorial parenchymal neoplasia of one institution over a 4-year period was included. Using high-resolution magnetic resonance imaging data, a detailed analysis of the topographic-anatomical tumor features was performed. Differences between neuroepithelial tumors, primary central nervous system lymphoma (PCNSL) and metastases were assessed using pairwise comparisons adjusted for multiple testing, upon significance of the omnibus test. RESULTS: Based on image analysis of 648 patients-419 (65%) neuroepithelial tumors, 28 (5%) PCNSL and 201 (31%) metastases-entity-specific topographic-anatomical patterns were identified. Neuroepithelial tumors showed a radial ventriculo-cortical orientation, inconsistent with the current belief of a growth along white matter tracts, whereas the pattern in PCNSL corresponded to a growth along such. Metastases preferentially affected the cortex and subcortical white matter of large arteries' terminal supply areas. This study provides a comprehensive anatomical description of the topography of NT, PCNSL and metastases intended to serve as a topographic reference for clinicians and neuroscientists. CONCLUSIONS: The identified distinct anatomical patterns provide evidence for a specific interaction between tumor and anatomical structures, following a pathoclitic concept. Understanding differences in their anatomical behavior has the potential to improve our pathophysiological understanding and to tailor therapy of brain tumors.

Repeated craniotomies for intracranial tumors: is the risk increased? Pooled analysis of two prospective, institutional registries of complications and outcomes.

PURPOSE: Deciding whether to re-operate patients with intracranial tumor recurrence or remnant is challenging, as the data on safety of repeated procedures is limited. This study set out to evaluate the risks for morbidity, mortality, and complications after repeated operations, and to compare those to primary operations. METHODS: Retrospective observational two-center study on consecutive patients undergoing microsurgical tumor resection. The data derived from independent, prospective institutional registries. The primary endpoint was morbidity at 3 months (M3), defined as significant decrease on the Karnofsky Performance Scale (KPS). Secondary endpoints were mortality, rate and severity of complications according to the Clavien-Dindo Grade (CDG). RESULTS: 463/2403 (19.3%) were repeated procedures. Morbidity at M3 occurred in n = 290 patients (12.1%). In univariable analysis, patients undergoing repeated surgery were 98% as likely as patients undergoing primary surgery to experience morbidity (OR 0.98, 95% CI 0.72-1.34, p = 0.889). In multivariable analysis adjusted for age, sex, tumor size, histology and posterior fossa location, the relationship remained stable (aOR 1.25, 95% CI 0.90-1.73, p = 0.186). Mortality was n = 10 (0.4%) at discharge and n = 95 (4.0%) at M3, without group differences. At least one complication occurred in n = 855, and the rate (35.5% vs. 35.9%, p = 0.892) and severity (CDG; p = 0.520) was similar after primary and repeated procedures. Results were reproduced in subgroup analyses for meningiomas, gliomas and cerebral metastases. CONCLUSIONS: Repeated surgery for intracranial tumors does not increase the risk of morbidity. Mortality, and both the rate and severity of complications are comparable to primary operations. This information is of value for patient counseling and the informed consent process.

Patterns of care: burr-hole cover application for chronic subdural hematoma trepanation.

OBJECTIVE: Skin depressions may appear as undesired effects after burr-hole trepanation for the evacuation of chronic subdural hematomas (cSDH). Placement of burr-hole covers to reconstruct skull defects can prevent skin depressions, with the potential to improve the aesthetic result and patient satisfaction. The perception of the relevance of this practice, however, appears to vary substantially among neurosurgeons. The authors aimed to identify current practice variations with regard to the application of burr-hole covers after trepanation for cSDH. METHODS: An electronic survey containing 12 questions was sent to resident and faculty neurosurgeons practicing in different parts of the world, as identified by an Internet search. All responses completed between September 2018 and December 2018 were considered. Descriptive statistics and logistic regression were used to analyze the data. RESULTS: A total of 604 responses were obtained, of which 576 (95.4%) provided complete data. The respondents' mean age was 42.4 years (SD 10.5), and 86.5% were male. The sample consisted of residents, fellows, junior/senior consultants, and department chairs from 79 countries (77.4% Europe, 11.8% Asia, 5.4% America, 3.5% Africa, and 1.9% Australasia). Skin depressions were considered a relevant issue by 31.6%, and 76.0% indicated that patients complain about skin depressions more or less frequently. Burr-hole covers are placed by 28.1% in the context of cSDH evacuation more or less frequently. The most frequent reasons for not placing a burr-hole cover were the lack of proven benefit (34.8%), followed by additional costs (21.9%), technical difficulty (19.9%), and fear of increased complications (4.9%). Most respondents (77.5%) stated that they would consider placing burr-hole covers in the future if there was evidence for superiority of the practice. The use of burr-hole covers varied substantially across countries, but a country's gross domestic product per capita was not associated with their placement. CONCLUSIONS: Only a minority of neurosurgeons place burr-hole covers after trepanation for cSDH on a regular basis, even though the majority of participants reported complaints from patients regarding postoperative skin depressions. There are significant differences in the patterns of care among countries. Class I evidence with regard to patient satisfaction and safety of burr-hole cover placement is likely to have an impact on future cSDH management.

Improving the aesthetic outcome with burr hole cover placement in chronic subdural hematoma evacuation-a retrospective pilot study.

BACKGROUND: The aesthetic outcome after burr hole trepanation for the evacuation of chronic subdural hematomas (cSDH) is often unsatisfactory, as the bony skull defects may cause visible skin depressions. The purpose of this study was to evaluate the efficacy of burr hole cover placement to improve the aesthetic outcome. METHODS: We reviewed consecutive patients treated by burr hole trepanation for cSDH with or without placement of burr hole covers by a single surgeon between October 2016 and May 2018. The clinical data, including complications, were derived from the institution's prospective patient registry. The primary endpoint was the aesthetic outcome, as perceived by patients on the aesthetic numeric analog (ANA) scale, assessed by means of a standardized telephone interview. Secondary endpoints were skin depression rates and wound pain, as well as complications. RESULTS: From n = 33, outcome evaluation was possible in n = 28 patients (n = 24 male; mean age of 70.4 ± 16.1 years) with uni- (n = 20) or bilateral cSDH (n = 8). A total of 14 burr hole covers were placed in 11 patients and compared to 50 burr holes that were not covered. Patient satisfaction with the aesthetic outcome was significantly better for covered burr holes (mean ANA 9.3 ± 0.74 vs. 7.9 ± 1.0; p < 0.001). Skin depressions occurred over 7% (n = 1/14) of covered and over 92% (n = 46/50) of uncovered burr holes (p < 0.001). There was no difference in wound pain (p = 0.903) between covered and uncovered sites. No surgical site infection, cSDH recurrence, or material failure was encountered in patients who had received a burr hole plate. CONCLUSIONS: In this retrospective series, placement of burr hole covers was associated with improved aesthetic outcome, likely due to reduction of skin depressions. A randomized controlled trial is developed to investigate whether adding burr hole covers results in superior aesthetic outcomes, without increasing the risk for complications.

Epigenetic modification and characterization of the MGMT promoter region using CRISPRoff in glioblastoma cells.

The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) promoter region is a critical predictor of response to alkylating agents in glioblastoma. However, current approaches to study the MGMT status focus on analyzing models with non-identical backgrounds. Here, we present an epigenetic editing approach using CRISPRoff to introduce site-specific CpG methylation in the MGMT promoter region of glioma cell lines. Sanger sequencing revealed successful introduction of methylation, effectively generating differently methylated glioma cell lines with an isogenic background. The introduced methylation resulted in reduced MGMT mRNA and protein levels. Furthermore, the cell lines with MGMT promoter region methylation exhibited increased sensitivity to temozolomide, consistent with the impact of methylation on treatment outcomes in patients with glioblastoma. This precise epigenome-editing approach provides valuable insights into the functional relevance of MGMT promoter regional methylation and its potential for prognostic and predictive assessments, as well as epigenetic-targeted therapies.

Immunological and tumor-intrinsic mechanisms mediate the synergistic growth suppression of experimental glioblastoma by radiotherapy and MET inhibition.

The hepatocyte growth factor (HGF)/MET signaling pathway has been proposed to be involved in the resistance to radiotherapy of glioblastoma via proinvasive and DNA damage response pathways.Here we assessed the role of the MET pathway in the response to radiotherapy in vitro and in vivo in syngeneic mouse glioma models. We find that the murine glioma cell lines GL-261, SMA-497, SMA-540 and SMA-560 express HGF and its receptor MET and respond to exogenous HGF with MET phosphorylation. Glioma cell viability or proliferation are unaffected by genetic or pharmacological MET inhibition using tepotinib or CRISPR/Cas9-engineered Met gene knockout and MET inhibition fails to sensitize glioma cells to irradiation in vitro. In contrast, the combination of tepotinib with radiotherapy prolongs survival of orthotopic SMA-560 or GL-261 glioma-bearing mice compared with radiotherapy or tepotinib treatment alone. Synergy is lost when such experiments are conducted in immunodeficient Rag1-/- mice, and, importantly, also when Met gene expression is disrupted in the tumor cells. Combination therapy suppresses a set of pro-inflammatory mediators including matrix metalloproteases that are upregulated by radiotherapy alone and that have been linked to poor outcome in glioblastoma. Several of these mediators are positively regulated by transforming growth factor (TGF)-ß, and pSMAD2 levels as a surrogate marker of TGF-ß pathway activity are suppressed by combination treatment. We conclude that synergistic suppression of experimental syngeneic glioma growth by irradiation and MET inhibition requires MET expression in the tumor as well as an intact immune system. Clinical evaluation of this combined strategy in newly diagnosed glioblastoma is warranted.

Meta-topologies define distinct anatomical classes of brain tumours linked to histology and survival.

The current World Health Organization classification integrates histological and molecular features of brain tumours. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumours. We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumour profiles of 936 patients with neuroepithelial tumours and brain metastases. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumour patterns, termed meta-topologies. The optimal part-based representation was automatically determined in 10 000 split-half iterations. We further characterized each meta-topology's unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns. In neuroepithelial tumours, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumours. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.Using a novel data-driven approach, we identified generalizable topological patterns in both neuroepithelial tumours and brain metastases. Differences in the histopathologic profiles and prognosis of these anatomical tumour classes provide insights into the heterogeneity of tumour biology and might add to personalized clinical decision-making.

Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.

COveRs to impRove EsthetiC ouTcome after Surgery for Chronic subdural hemAtoma by buRr hole trepanation-Results of a Swiss Single-Blinded, Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Burr hole trepanation to evacuate chronic subdural hematoma (cSDH) results in bony skull defects that can lead to skin depressions. We intend to study the effect of burr hole covers to prevent skin depressions and improve the esthetic result. METHODS: In a randomized trial, we enrolled adult patients with symptomatic cSDH. Patients received burr hole trepanation with (intervention) vs without burr hole covers (control) in a 1:1 ratio. Patients requiring evacuation of bilateral cSDHs served as their internal control. Primary outcome was satisfaction with the esthetic result of the scar, measured from 0 (dissatisfied) to 10 (very satisfied) on the Esthetic Numeric Analog (ANA) scale at 90 days. Secondary outcomes included ANA scale, rates of skin depression, complications, as well as neurological, disability, and health-related quality of life outcomes until 12 months. RESULTS: We included 78 patients (55 with unilateral and 23 with bilateral cSDH; median age 78 years, 83% male) between 03/2019 and 05/2021, 50 trepanations for the intervention and 51 for the control group. In an intention-to-treat analysis, the ANA scale scores were 9.0 (intervention) and 8.5 (control arm) at 90 days (P = .498). At 12 months, the ANA scale scores were 9.0 and 8.0 for the intervention and control groups, respectively (P = .183). Skin depressions over the frontal burr hole were noted by 35% (intervention) and 63% (control) of patients at 90 days (P = .009) and by 35% and 79% (P < .001) at 12 months, respectively. There were no differences in complications, neurological, disability, and health-related quality of life outcomes. CONCLUSION: Satisfaction with the esthetic result of the scar was inherently high. This study does not show evidence for improvement on the ANA scale by applying a burr hole cover. The application of burr hole covers resulted in less skin depressions and did not negatively affect complication rates or outcomes.

A prognostic model for tumor recurrence and progression after meningioma surgery: preselection for further molecular work-up.

Purpose: The selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up. Methods: All patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence. Results: Out of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 - 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value < 0.001). Conclusion: The proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting.

Multimodal anatomy of the human forniceal commissure.

Ambiguity surrounds the existence and morphology of the human forniceal commissure. We combine advanced in-vivo tractography, multidirectional ex-vivo fiber dissection, and multiplanar histological analysis to characterize this structure's anatomy. Across all 178 subjects, in-vivo fiber dissection based on the Human Connectome Project 7 T MRI data identifies no interhemispheric connections between the crura fornicis. Multidirectional ex-vivo fiber dissection under the operating microscope demonstrates the psalterium as a thin soft-tissue membrane spanning between the right and left crus fornicis, but exposes no commissural fibers. Multiplanar histological analysis with myelin and Bielchowsky silver staining, however, visualizes delicate cruciform fibers extending between the crura fornicis, enclosed by connective tissue, the psalterium. The human forniceal commissure is therefore much more delicate than previously described and presented in anatomical textbooks. This finding is consistent with the observed phylogenetic trend of a reduction of the forniceal commissure in non-human primates compared to non-primate eutherian mammals.

Association of perioperative adverse events with subsequent therapy and overall survival in patients with WHO grade III and IV gliomas.

Background: Maximum safe resection followed by chemoradiotherapy as current standard of care for WHO grade III and IV gliomas can be influenced by the occurrence of perioperative adverse events (AE). The aim of this study was to determine the association of AE with the timing and choice of subsequent treatments as well as with overall survival (OS). Methods: Prospectively collected data of 283 adult patients undergoing surgery for WHO grade III and IV gliomas at the University Hospital Zurich between January 2013 and June 2017 were analyzed. We assessed basic patient characteristics, KPS, extent of resection, and WHO grade, and we classified AE as well as modality, timing of subsequent treatment (delay, interruption, or non-initiation), and OS. Results: In 117 patients (41%), an AE was documented between surgery and the 3-month follow-up. There was a significant association of AE with an increased time to initiation of subsequent therapy (p = 0.005) and a higher rate of interruption (p < 0.001) or non-initiation (p < 0.001). AE grades correlated with time to initiation of subsequent therapy (p = 0.038). AEs were associated with shorter OS in univariate analysis (p < 0.001). Conclusion: AEs are associated with delayed and/or altered subsequent therapy and can therefore limit OS. These data emphasize the importance of safety within the maximum-safe-resection concept.

Blood-brain barrier alterations in human brain tumors revealed by genome-wide transcriptomic profiling.

BACKGROUND: Brain tumors, whether primary or secondary, have limited therapeutic options despite advances in understanding driver gene mutations and heterogeneity within tumor cells. The cellular and molecular composition of brain tumor stroma, an important modifier of tumor growth, has been less investigated to date. Only few studies have focused on the vasculature of human brain tumors despite the fact that the blood-brain barrier (BBB) represents the major obstacle for efficient drug delivery. METHODS: In this study, we employed RNA sequencing to characterize transcriptional alterations of endothelial cells (EC) isolated from primary and secondary human brain tumors. We used an immunoprecipitation approach to enrich for EC from normal brain, glioblastoma (GBM), and lung cancer brain metastasis (BM). RESULTS: Analysis of the endothelial transcriptome showed deregulation of genes implicated in cell proliferation, angiogenesis, and deposition of extracellular matrix (ECM) in the vasculature of GBM and BM. Deregulation of genes defining the BBB dysfunction module was found in both tumor types. We identified deregulated expression of genes in vessel-associated fibroblasts in GBM. CONCLUSION: We characterize alterations in BBB genes in GBM and BM vasculature and identify proteins that might be exploited for developing drug delivery platforms. In addition, our analysis on vessel-associated fibroblasts in GBM shows that the cellular composition of brain tumor stroma merits further investigation.

Adverse Events in Neurosurgery: The Novel Therapy-Disability-Neurology Grade.

BACKGROUND: The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits. OBJECTIVE: To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability. METHODS: The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries. RESULTS: Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced. CONCLUSION: Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.

Fitness-to-drive for glioblastoma patients: Guidance from the Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM).

OBJECTIVE: The management of brain tumour patients who would like to resume driving is complex, and needs multidisciplinary input and a consensus among treating physicians. The Swiss Neuro-Oncology Society (SwissNOS) and the Swiss Society for Legal Medicine (SGRM) aim to provide guidance on how to assess "fitness-to-drive" of glioblastoma patients and to harmonise the relevant procedures in Switzerland. METHODS: At several meetings, Swiss neuro-oncologists discussed common practices on how to advise patients with a stable, i.e., non-progressive, glioblastoma, who wish to resume driving after the initial standard tumour treatment. All participants of the SwissNOS meetings were invited twice to return a questionnaire (modified Delphi process) on specific tools/procedures they commonly use to assess "fitness-to-drive" of their patients. Answers were analysed to formulate a tentative consensus for a structured and reasonable approach. RESULTS: Consensus on minimum requirements for a "fitness-to-drive" programme for glioblastoma patients could be reached among Swiss neuro-oncologists. The recommendations were based on existing guidelines and expert opinions regarding patients with seizures, visual disturbances, cognitive impairment or focal deficits for safe driving. At this point in time, the Swiss neuro-oncologists agreed on the following requirements for glioblastoma patients after the initial standard therapy and without a seizure for at least 12 months: (1) stable cranial magnetic resonance imaging (MRI) according to Response Assessment in Neuro-Oncology (RANO) criteria, to be repeated every 3 months; (2) thorough medical history, including current or new medication, a comprehensive neurological examination at baseline (T0) and every 3 months thereafter, optionally an electrocencephalogram (EEG) at baseline; (3) ophthalmological examination including visual acuity and intact visual fields; and (4) optional neuropsychological assessment with a focus on safe driving. Test results have to be compatible with safe driving at any time-point. Patients should be informed about test results and optionally sign a document. CONCLUSIONS: We propose regular thorough clinical neurological examination and brain MRI, optional EEG, neuropsychological and visual assessments to confirm "fitness-to-drive" for glioblastoma patients after initial tumour-directed therapy. The proposed "fitness-to-drive" assessments for glioblastoma patients serves as the basis for a prospective Swiss Pilot Project GLIODRIVE (BASEC ProjectID 2020-00365) to test feasibility, adherence and safety in a structured manner for patients who wish to resume driving. Research will focus on confirming the usefulness of the proposed tools in predicting "fitness-to-drive" and match results with events obtained from the road traffic registry (Strassenverkehrsamt).

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors.

Introduction: The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question: This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods: A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results: The total sample of 4864 patients had a mean age of 56.4 â€‹± â€‹14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. Discussion: Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion: Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.